Parkinson's disease (PD) is one of the most common age-related neurodegenerative disorders. PD is characterised by the selective loss of dopaminergic neurones in the substantia nigra (SN), and the loss of dopamine in the striatum accompanied by the presence of Lewy bodies. Nigral neurodegeneration is also a feature of diseases termed ‘Parkinson-plus syndromes’ such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). The main symptoms of iPD are tremor, rigidity of the limbs and trunk, akinesia, bradykinesia and postural abnormalities, and the severity of these symptoms differs amongst individuals. The initiating cause of PD still remains unknown and therefore investigations into other elements that can initiate neurodegeneration in the SN are being looked into.
Osteopontin (OPN) has been shown to play an important function in oxidative and nitrative stress, in inflammatory processes, in apoptotic pathways as well as possessing calcium binding properties. OPN is a secreted glycosylated phosphoprotein. The size of the secreted protein varies between 44 -75 kDa and this is due to differences in post-translational modifications. Variations in glycosylation, phosphorylation, sulphation and thrombin cleavage lead to the generation of differing functional forms of OPN.
The two main receptor types that OPN binds to are the integrin receptors and the CD44 receptors. The integrin receptors are heterodimeric transmembrane proteins formed by non-covalent binding of α and β subunits. OPN binds to integrin receptors in either an RGD-dependent or RGD-independent manner. The following integrins bind to the RGD binding motif in OPN: α5β1, α8β1, αvβ1, αvβ3 and αvβ5. The RGD-independent integrins are the α4β1 receptor and the α9β1 receptor which bind via the SVVYGLR sequence, although these receptors only recognise the thrombin cleaved fragment of OPN and not the full length protein. OPN appears to have the highest affinity for the αvβ3 receptor.
OPN is constitutively expressed in bone, kidney, brain and blood. In response to a variety of stimuli such as oxidative stress, heat shock and inflammation, OPN can be induced in a wide variety of cells including, epithelial cells, smooth muscle cells, fibroblasts, macrophages, T-lymphocytes and microglial cells. OPN is a multifunctional protein with new functions continuously being discovered. This is due to the existence of numerous, functionally distinct forms, that can differ at the transcriptional level as well as at the post-transitional modification level. In addition, its functions differ according to whether it is present as an immobilised cell adhesion protein or as a soluble protein. OPN is known to regulate cell death, cell survival, migration and tissue remodelling. Elevated OPN expression has been found in a variety of diseases including multiple sclerosis (MS), atherosclerosis, myocardial injury, tuberculosis, osteoarthritis, rheumatoid arthritis and various cancers.
To date there have been no studies on the relationship between OPN and neurodegenerative diseases, although OPN mRNA has been shown to be expressed in the substantia nigra (SN) in the rat and, therefore, it is possible that OPN may be involved in the pathogenic processes that occur in PD.
OPN is able to regulate cytokine levels and act as a glial cell activator and chemoattractant. There is also evidence for an inflammatory aspect in the pathogenesis of PD. However, it is not yet known whether glial cell activation is a cause or a consequence of neurodegeneration in PD.